Retinoids are being used in the treatment of several malignancies and precancerous lesions. Their effects on cell lines derived from solid tumors, such as breast cancer, have also been described extensively. Their benefit in breast cancer, however, remains unclear. This might be because of the high levels of heterogeneity of breast tumors and the very variable response to the antiproliferative effects of retinoic acid. In mammary tumor cell lines, the response to retinoic acid is highly correlated with the expression of the estrogen receptor alpha (ERα), which regulates the expression of the retinoic acid receptor alpha gene RARA. However, some ER-negative cell lines, such as the HER2 positive SK-BR-3 cell line, have been reported to be RA-sensitive.
In Chapter 2: of this thesis we have investigated the mechanisms of ER-dependent and ER-independent RA signaling in breast cancer cells. Using ER-positive and ER-negative cell lines, we show that part of the response to RA is independent of ER signaling. Several direct retinoic acid targets were identified that could mimic antiproliferative effects of retinoic acid when overexpressed in breast cancer cells. This study has provided better insight in the complex mechanisms that lead to RA-induced growth arrest in breast cancer cells.
In Chapter 3: we looked further into the ER-independent RA signaling in HER2/RARA-amplified cells and identified a synergy between RA and Herceptin in these cells. We propose a role for FOXOs in mediating this synergy. HER2/RARA coamplified breast tumors might represent a subclass of tumors that could benefit from retinoid treatment, both increase antitumor effects of Herceptin, as well as in potentially reducing Herceptin resistance.
In conclusion, data presented in this thesis give better insight in the mechanisms of RA induced growth arrest in breast cancer cells and provide a potential application of retinoids in a subset of breast tumors.